General knowledge about Immunoglobulin G: Immunoglobulin G (IgG) are antibody molecules. IgG is the most abundant immunoglobulin and is approximately equally distributed in blood and in tissue fluids, constituting the main portion of serum immunoglobulins in mammalian animals and in humans. IgG molecules are synthesized and secreted by plasma B cells.
IgG antibodies are predominantly involved in the secondary immune response. The presence of specific IgG generally corresponds to maturation of the antibody response. IgG is the only antibody isotype that can pass through the human placenta, thereby providing protection to the foetus in the uterus. Along with IgA secreted in the breast milk, residual IgG absorbed through the placenta provides the neonate with humoral immunity before its own immune system develops.
IgG can bind to many kinds of pathogens, for example viruses, bacteria, and fungi, and protects the body against them by agglutination and immobilization, complement activation (classical pathway), opsonization for phagocytosis and/or neutralization of their toxins. It also plays an important role in Antibody-dependent cell-mediated cytotoxicity (ADCC).
The mammalian IgG generating immune responses are strongly connected with others and immune response cascades and signalling pathways. So that hapten or immunogen motives and receptors, and receptor families correlate and regulate in many known and un-known ways in mammalian individuals, individually.
This is why any biologically active agent introduced as a therapeutic agent may introduce immune response, desired and undesired even after many individual dosages.
WO 2007/048599 describes particulate drug delivery systems based on a polymeric carrier, characterized in that at least one signal substance for transport through a biological barrier and at least one active ingredient are included, with carrier, signal substance and active ingredient showing no covalent linkages with one another. The signal substance is lactoferrin or a peptide derived from lactoferrin.
In a particularly preferred embodiment, a signal peptide is selected from the group of peptides having an amino acid sequence
(SEQ ID NO: 1)KCFQWQRNMRKVRGPPVSCIKR,(SEQ ID NO: 3 in WO 2007/048599) (SEQ ID NO: 2)CFQWQRNMRKVRGPPVSC,(SEQ ID NO: 4 in WO 2007/048599) (SEQ ID NO: 3)FQWQRNMRKVRGPPVS,(SEQ ID NO: 5 in WO 2007/048599) (SEQ ID NO: 4)FQWQRNMRKVR,(SEQ ID NO: 6 in WO 2007/048599) (SEQ ID NO: 5)KCRRWQWRMKKLGAPSITCVRR(SEQ ID NO: 29 in WO 2007/048599)and (SEQ ID NO: 6)CRRWQWRMKKLGAPSITC(SEQ ID NO: 30 in WO 2007/048599)or a derivative thereof.
In a preferred embodiment, the cell-penetrating peptides of WO 2007/048599 are comprising an amino acid sequence as shown in SEQ ID NOS: 3, 4, 29 or 30 of WO 2007/048599 or a corresponding sequence with an identity of at least 40%, preferably of at least 50%, particularly preferably with an identity of more than 75% or better of more than 90%.
WO 2007/076904A1 describes a peptide having an amino acid sequence comprising at least 8 consecutive amino acids of the human lactoferrin protein or of the bovine lactoferrin protein, whereby the peptide is suitable to act as a cell-penetrating peptide. Many of the peptides mentioned in WO 2007/076904A1 and in WO 2007/048599 are identical.
The most promising cell-penetrating peptide in WO 2007/076904A1 with the best effects in the examples is KCFQWQRNMRKVRGPPVSCIKR (SEQ ID NO: 3 in WO 2007/076904A1, SEQ ID NO: 1 herein).
The lactoferrin derived cell-penetrating peptides are intended to permit the transport of cargo molecules, which are active pharmaceutical ingredients such as DNA, RNA, peptides or antigens for vaccination, which may be orally ingested, through the biological membranes and thus allow efficient uptake of these molecules in the human or animal organism.